CASE REPORT Open Access

Tumor control with PD-1 inhibition ina patient with concurrent metastaticmelanoma and renal cell carcinomaMelina E. Marmarelis1, Meredith R. Davis1, Nilay S. Sethi1, Katherine M. Krajewksi2, Rana R. McKay1, Toni K. Choueiri1

and Patrick A. Ott1*

Abstract

Blockade of the immunological checkpoint programmed death 1 (PD-1) using monoclonal antibodies has shownrobust anti-tumor activity across a broad range of solid and hematological malignancies including melanoma andrenal cell carcinoma (RCC). Characteristic markers such as the presence of tumor infiltrating lymphocytes, PD-L1 status,and mutational load may be equally or even more important in predicting clinical benefit from PD-1 pathway blockadethan tumor histology. This case of a patient with concurrent metastatic melanoma and metastatic RCC, both of whichwere controlled for more than a year after a single dose of the anti-PD-1 antibody pembrolizumab, illustratesthe potential to simultaneously treat distinct immunogenic tumors with anti-PD-1 agents.

Keywords: PD-1, Immune checkpoint blockade, Antibody therapy, Melanoma, Renal cell cancer,Immunotherapy, Concurrent cancer

BackgroundImmune checkpoint blockade using monoclonal anti-bodies directed against negative regulators such ascytotoxic lymphocyte antigen-4 (CTLA-4) and pro-grammed death 1 (PD-1)/programmed death ligand 1(PD-L1) has emerged as a powerful strategy in thetreatment of different cancer types [1–3]. Both CTLA-4 and PD-1 are cell surface receptors that negativelyregulate the immune response and their blockade caninduce or enhance anti-tumor T cell activity. The anti-CTLA-4 monoclonal antibody ipilimumab demon-strated a survival benefit in Phase III studies for thefirst time in patients with advanced melanoma [2, 4],leading to approval in several countries. Durable tumorresponses in patients with advanced melanoma beingtreated with ipilimumab yielded a plateau in the sur-vival curve at 21 % 3 years out from study initiation[5]. Inhibition of the PD-1/PD-L1 pathway showed ob-jective response rates of up to 40 % and superior overall

survival when compared to ipilimumab in advanced mel-anoma [6]. Strikingly, as opposed to the relatively modestanti-tumor activity of ipilimumab outside of melanoma,PD-1 pathway inhibition is efficacious against a widespectrum of solid and hematological malignancies includ-ing RCC, non-small cell lung cancer, bladder cancer, andHodgkin’s lymphoma. There is evidence that tumorcharacteristics such as the presence of an immune cellinfiltrate, expression of PD-L1 on tumor and/or immunecells, and an elevated mutational load with correspondingexpression of neoantigens are predictive of anti-tumoractivity with PD-1 pathway inhibition [7–10]. The broadanti-tumor activity of PD-1 pathway blockade suggeststhat it may be effective against different tumors present inone individual. These considerations may be critical indesigning a treatment plan for a patient with metastasesfrom different primary tumors, which poses a particularchallenge in current cancer therapeutics. Here, we presenta patient with concurrent metatstatic melanoma andRCC who achieved disease control of both malignan-cies after a single dose of the anti-PD-1 monoclonalantibody pembrolizumab.* Correspondence: Patrick_Ott@dfci.harvard.edu

1Department of Medical Oncology, Dana Farber Cancer Institute, Brighamand Women’s Hospital, and Harvard Medical School, Boston, MA, USAFull list of author information is available at the end of the article

© 2016 Marmarelis et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, andreproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link tothe Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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Case presentationA 73-year-old man was diagnosed with T1a melanomaarising from the right shoulder in 2009. He underwent awide excision and sentinel lymph node biopsy. Pathologyreview revealed a 1.64 mm melanoma, anatomic level deepIII/early IV, no ulceration, 1 mitosis/mm2. Four right axil-lary sentinel lymph nodes were negative for involvementwith melanoma. In September 2013, after experiencinghematuria, the patient underwent a cystoscopy followed bytransurethral resection of a bladder tumor (TURBT), which

revealed a low-grade urothelial carcinoma with no evidenceof bladder invasion. He is a lifelong non-smoker. A stagingcomputerized tomography (CT) scan revealed two rightlower lobe lung nodules (2.7 cm and <1 cm), and a 6.3 cmtumor in the left kidney. A positron emission tomographycomputerized tomography (PET/CT) in November 2013(Fig. 1) showed enlarged mediastinal lymph nodes inaddition to FDG uptake in the lung nodules and a complexleft kidney mass. A mass in the thoracic spine (T3 vertebra)and a small focus of uptake in the right sacral ala were also

11/11/13 PET/CT: Enlarged mediastinal nodes, RLL lung nodule (path melanoma), complex left kidney mass, T3 vertebra lesion (pathology RCC)

1/17/14: Ipilimumab

2/7/14 : Ipilimumab+bevacizumab

2/28/18, 3/21/14: Ipilimumab

4/21/14 PET/CT: Progressive disease (new adrenal lesion)

5/19/14 PET/CT:SD

7/14/14 PET/CT:Mixed response

7/29/14: Pembrolizumab, 2mg/kg x1

8/19/14:Pembrolizumabdiscontinued 2nd

immune-related hepatitis

11/24/14 CT:PR/SD

2/23/15 CT: PR/SD

5/20/15 CT: PR/SD

8/26/15 CT:PR/SD

11/10/15 CT: PD

Fig. 1 Timeline of events and treatment. CT = computerized tomography. PET = positron emission tomography. RLL = right lower lobe. RCC = renalcell carcinoma

Fig. 2 a PET CT demonstrating FDG uptake in an enlarged mediastinal lymph nodes, small right lower lobe lung nodule, exophytic heterogenousmass in left kidney and a 3.5 × 3.2 cm vertebral mass at T3 with SUV of 11.4. b Enhanced CT view of the T3 vertebral mass

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noted (Fig. 2). A biopsy of the T3 vertebral lesion was per-formed and pathologic review demonstrated RCC. A coreneedle biopsy of one of the right lower lobe lung noduleswas also performed and unexpectedly revealed recurrentmetastatic melanoma (Fig. 3). In December 2013, a brainMRI showed a subcentimeter left temporal metastasis. Thepatient received radiation to the T3 vertebral metastasisand stereotactic radiosurgery to the brain metastasis.While weighing the treatment options for these two

cancers, although our initial thoughts were to focus onthe more aggressive melanoma (BRAF and NRAS wildtype), we were motivated to design a therapy regimenthat could yield efficacious responses against both can-cers. Bevacizumab, the anti-Vascular Endothelial DerivedGrowth Factor (VEGF) directed monoclonal antibodyapproved for use in renal cell carcinoma, has some effi-cacy in advanced melanoma and was found to be safeand potentially synergistic with ipilimumab [11, 12]. Theurothelial cancer was not addressed therapeuticallybecause of the metastatic melanoma and RCC takingprecedence. Based on this data, the patient received onecycle of ipilimumab at the standard dose of 3 mg/kg.Following insurance approval, he then received a cycle

of ipilimumab in combination with bevacizumab 15 mg/kg every 3 weeks. Shortly after receiving the combin-ation, the patient presented with a left sided headache,blurred vision in the left eye, and left eyelid ptosis. Abrain MRI revealed a subacute hemorrhage at the site ofthe previously irradiated left temporal metastasis. A tem-poral artery biopsy was negative for temporal arteritis. Theremainder of ipilimumab therapy (3rd and 4th dose) wasadministered without concurrent Bevacizumab given theconcern that VEGF inhibition may have possibly contrib-uted to the brain hemorrhage. The ipilimumab treatmentcourse was also complicated by immune-related hypophy-sitis resulting in adrenal insufficiency, which was success-fully treated with hydrocortisone.Serial PET/CTs showed progressive disease in April

2014. Repeat PET/CT performed in July of 2014 onceagain revealed disease evolution with increased FDG avid-ity of a dominant right lower lobe lung mass, increasedsize and avidity of a right adrenal lesion, and increasedFDG avidity of the left sided renal mass. Based on these re-sults and the availability on an Expanded Access Program,treatment with the anti-PD-1 antibody pembrolizumab at2 mg/kg every 3 weeks was initiated in July of 2014. After

Fig. 3 Pathology of T3 vertebral mass and right lower lobe lung lesions. Pathology of the T3 vertebral mass biopsy represents a metastasis fromrenal cell carcinoma, the lung lesion is consistent with a metastasis from melanoma. (1) Immunohistochemistry markers of the T3 vertebral massand the right lower lobe (RLL) lung nodule. (2) T3 vertebral lesion: a. low power b. high power c. CAM5.2 d. Pax-8 (3) RLL lesion: a. high power b.Cytokeratin (CK7) c. S100 d. Melan-A e. HMB45

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one dose, the patient developed grade 3 transaminitis(ALT > 7x ULN, AST >11x ULN, total bilirubin normal),prompting discontinuation of treatment due to presumedimmune-related hepatitis. Intravenous solumedrol was ad-ministered for the treatment of immune-related hepatitis.A liver biopsy performed six days into the steroid taper(prednisone 80 mg BID for the six days prior to biopsy)showed pathological features compatible with but notdiagnostic of immune-related hepatitis. Liver functiontests normalized fifteen days after the initial diagnosis andremained within reference range after completion of afour-week prednisone taper.Restaging CTs of the chest, abdomen, and pelvis per-

formed in September 2014 demonstrated dramatic re-duction in size of several lung metastases, while othersremained stable. The right adrenal lesion, several mes-enteric nodules, and a subcutaneous nodule on the leftanterior abdominal wall were all substantially smallerin size. The left renal mass remained stable. Serial CTsof the chest, abdomen, and pelvis in November 2014,February 2015, May 2015, and August 2014 showedcontinued decrease in tumor size consistent with a partialresponse to treatment for a duration of 14 months (Fig. 4).Most recently, a chest, abdomen, and pelvic CT inNovember of 2015 showed two new subcentimeter pul-monary lesions and a satellite nodule in the primary renal

cell cancer. The patient is currently undergoing re-induction therapy with pembrolizumab.

ConclusionWe describe a patient with concurrent biopsy-provenmetastatic melanoma and RCC who was treated with onedose of pembrolizumab that was complicated by immune-related hepatitis but nevertheless lead to a durable tumorresponse in both melanoma and RCC.While the presence of two distinct metastatic processes

was established by biopsy (melanoma in the lung andRCC in the spine at level T3), the contribution of eachtumor to the overall metastatic burden cannot be deter-mined. However, since at least one (and likely more) lunglesion(s) represent melanoma and the left renal lesion rep-resent RCC by imaging criteria, ongoing disease control ofboth cancers was evident on serial imaging. It is notablethat the patient developed immune-related hepatitis afteronly one dose of pembrolizumab. Immune-related toxicitymay be associated with a favorable outcome in patientstreated with CTLA-4 and/or PD-1 inhibition [13].Multiple primary cancers, which is defined as the

development of another primary cancer after diagnosisof an initial one (index cancer) in a given individual, is arelatively common occurrence. Interestingly, urinarybladder cancer is the most frequent index cancer in

PET CT Pre Pembrolizumab

CTPost Pembrolizumab

Mediastinal mass

Pulmonary lesion

Renal Mass

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b

-100

-80

-60

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-20

0

20

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60

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0 2 4 7 10 13 16

Mediastinal Mass RLL mass L RCC

Cha

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Fig. 4 a PET CT images of the mediastinal mass, pulmonary lesion and renal mass. Left column: Pre- pembrolizumab; right column: 8 weeks afteradministration of one dose of pembrolizumab. There is near complete involution of the anterior mediastinal mass and a decrease in size of thepulmonary lesion. The size of the renal mass is unchanged. b Size (cm) on axial imaging (CT or PET/CT) of renal, mediastinal and dominant rightpulmonary nodule over time. The last scan showed two new subcentimter pulmonary metastases and increased size of a soft tissue componentof the left renal mass

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patients with multiple primary cancers (18 %), whereas10 % of patients with RCC and melanoma, respectively de-velop a second primary [14]. No reliable data are available,to our knowledge, on frequencies of multiple primariesthat have metastasized concurrently such as in our pa-tient. It is interesting in this context that the patient’sdiagnosis of a localized low grade urothelial carcinoma ofthe bladder immediately preceded the patient’s diagnosisof metastatic melanoma and RCC. While the non-muscleinvasive bladder cancer lead to the diagnosis of melanomaand RCC in our patient, it appears unlikely that the blad-der cancer contributed to the metastatic disease burden inthis patient. Since bladder cancer has also been found tobe responsive to PD-1 pathway inhibition, the possibilitythat a third solid tumor may also have been controlled byPD-1 blockade in our patient is nevertheless an intriguingconsideration [8].PD-1 blockade reverts the PD-1 receptor-mediated dys-

functional state of effector memory T cells that have infil-trated the tumor into an active, functional state, therebyenabling tumor cell killing. These T cells are presumablyendogenously primed and specific for antigens expressedon the respective tumor they traffic into. It thereforeappears more likely that these T cells recognize tumor an-tigens that are distinct between the melanoma and theRCC rather than shared antigens. Although the immuneresponse may be distinct in RCC and melanoma, a certainpercentage of these tumors are immunogenic and there-fore potentially responsive to immune checkpoint block-ade [15]. This case illustrates that despite these distinctimmune responses, PD-1 inhibition may be a suitabletreatment option for patients with concurrent immune-responsive cancers.

ConsentClinical data for this case report were collected under in-stitutional review board approval (Dana-Farber/HarvardCancer Center #05-042).

Consent to publishWritten informed consent was obtained from the patientfor publication of this case report and any accompanyingimages.

AbbreviationsCT: computerized tomography; CTLA-4: cytotoxic lymphocyte antigen-4;MRI: Magnetic Resonance Imaging; PD-1: immunological checkpointprogrammed death; PD-L1: programmed death ligand 1; PET/CT: Positronemission tomography computerized tomography; RCC: renal cell carcinoma;TURBT: transurethral resection of a bladder tumor; VEGF: Vascular EndothelialDerived Growth Factor.

Competing interestsTKC reports grants from Bristol-Myers Squibb, grants and personal fees fromGlaxoSmithKline, grants and personal fees from Novartis, grants from Exelixis,Inc., grants and personal fees from Pfizer, grants and personal fees from Merck,grants from Roche, grants and personal fees from AstraZeneca, grants from

TRACON Pharmaceuticals, grants from Peloton, personal fees from Bayer,personal fees from Prometheus outside the submitted work. PAO reportsgrants and personal fees from Bristol-Myers Squibb, personal fees from Amgen,and grants from Merck and AztraZeneca/MedImmune outside of the submittedwork. All other authors have no conflicts to disclose.

Authors’ contributionsAuthor MM drafted the manuscript. MD helped to draft the manuscript andparticipated in the care of the patient. NS helped to draft the manuscriptand participated in the care of the patient. KMK provided and analyzed dataand helped to draft the manuscript, RM helped to draft the manuscript andparticipated in the care of the patient. TKC helped to coordinate the careof the patient and helped to draft the manuscript. PAO conceived of thereport, helped to draft the manuscript, and coordinated the care for thepatient. All authors read and approved the manuscript.

AcknowledgementWe thank Michelle Hirsch for providing pathology expertise and helpfuldiscussions and Jonathan Nowak for providing the pathology imagesincluded in the paper.

Author details1Department of Medical Oncology, Dana Farber Cancer Institute, Brighamand Women’s Hospital, and Harvard Medical School, Boston, MA, USA.2Department of Imaging, Dana Farber Cancer Institute, Brigham andWomen’s Hospital, and Harvard Medical School, Boston, MA, USA.

Received: 12 January 2016 Accepted: 4 April 2016

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